Cargando…

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined w...

Descripción completa

Detalles Bibliográficos
Autores principales: Tamaki, Sawako, Suzuki, Koichi, Abe, Iku, Endo, Yuhei, Kakizawa, Nao, Watanabe, Fumiaki, Saito, Masaaki, Tsujinaka, Shingo, Miyakura, Yasuyuki, Ohta, Satoshi, Tago, Kenji, Yanagisawa, Ken, Konishi, Fumio, Rikiyama, Toshiki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243030/
https://www.ncbi.nlm.nih.gov/pubmed/35768614
http://dx.doi.org/10.1038/s41598-022-15071-3
_version_ 1784738211807887360
author Tamaki, Sawako
Suzuki, Koichi
Abe, Iku
Endo, Yuhei
Kakizawa, Nao
Watanabe, Fumiaki
Saito, Masaaki
Tsujinaka, Shingo
Miyakura, Yasuyuki
Ohta, Satoshi
Tago, Kenji
Yanagisawa, Ken
Konishi, Fumio
Rikiyama, Toshiki
author_facet Tamaki, Sawako
Suzuki, Koichi
Abe, Iku
Endo, Yuhei
Kakizawa, Nao
Watanabe, Fumiaki
Saito, Masaaki
Tsujinaka, Shingo
Miyakura, Yasuyuki
Ohta, Satoshi
Tago, Kenji
Yanagisawa, Ken
Konishi, Fumio
Rikiyama, Toshiki
author_sort Tamaki, Sawako
collection PubMed
description Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT [half-maximal inhibitory concentration: 0.814 μM (control) vs. 0.332 μM (MC38 cells with a major satellite), p = 0.003] but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence.
format Online
Article
Text
id pubmed-9243030
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-92430302022-07-01 Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells Tamaki, Sawako Suzuki, Koichi Abe, Iku Endo, Yuhei Kakizawa, Nao Watanabe, Fumiaki Saito, Masaaki Tsujinaka, Shingo Miyakura, Yasuyuki Ohta, Satoshi Tago, Kenji Yanagisawa, Ken Konishi, Fumio Rikiyama, Toshiki Sci Rep Article Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT [half-maximal inhibitory concentration: 0.814 μM (control) vs. 0.332 μM (MC38 cells with a major satellite), p = 0.003] but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence. Nature Publishing Group UK 2022-06-29 /pmc/articles/PMC9243030/ /pubmed/35768614 http://dx.doi.org/10.1038/s41598-022-15071-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tamaki, Sawako
Suzuki, Koichi
Abe, Iku
Endo, Yuhei
Kakizawa, Nao
Watanabe, Fumiaki
Saito, Masaaki
Tsujinaka, Shingo
Miyakura, Yasuyuki
Ohta, Satoshi
Tago, Kenji
Yanagisawa, Ken
Konishi, Fumio
Rikiyama, Toshiki
Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title_full Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title_fullStr Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title_full_unstemmed Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title_short Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
title_sort overexpression of satellite rnas in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243030/
https://www.ncbi.nlm.nih.gov/pubmed/35768614
http://dx.doi.org/10.1038/s41598-022-15071-3
work_keys_str_mv AT tamakisawako overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT suzukikoichi overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT abeiku overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT endoyuhei overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT kakizawanao overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT watanabefumiaki overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT saitomasaaki overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT tsujinakashingo overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT miyakurayasuyuki overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT ohtasatoshi overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT tagokenji overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT yanagisawaken overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT konishifumio overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells
AT rikiyamatoshiki overexpressionofsatelliternasinheterochromatininduceschromosomalinstabilityandreflectsdrugsensitivityinmousecancercells